A. Di Giannuario

The interaction of peripherally and centrally administered dexamethasone and RU 38486 on morphine analgesia in mice

1. Dexamethasone or RU 38486 were administered intraperitoneally or intracerebroventricularly to mice 10 or 120 min before morphine administration. The interaction of these drugs with the analgesic effects of morphine was examined using the hot plate test. 2. Dexamethasone i.p. pretreatment reduced analgesic responses to morphine injected 120 min but not 10 min after dexamethasone; i.c.v. injection of dexamethasone 10 and 120 min before morphine administration was effective in reducing morphine analgesia. 3. RU 38486 i.c.v. pretreatment (but not i.p. pretreatment) performed 120 (but not 10) min before morphine administration enhanced morphine analgesic effects. 4. These results, particularly the effects of drug interaction for i.c.v. administration, strongly confirm a central site for dexamethasone and RU 38486 action.

Dexamethasone-induced selective inhibition of the central μ opioid receptor: functional in vivo and in vitro evidence in rodents

1 Endogenous corticosteroids and opioids are involved in many functions of the organism, including analgesia, cerebral excitability, stress and others. Therefore, we considered it important to gain information on the functional interaction between corticosteroids and specific opioid receptor subpopulations. 2 We have found that systemic administration (i.p.) of the potent synthetic corticosteroid, dexamethasone, reduced the antinociception induced by the highly selective μ agonist, DAMGO or by less selective μ agonists morphine and β‐endorphin administered i.e.v., On the contrary dexamethasone exerted little or no influence on the antinociception induced by a δ1 agonist, DPDPE and a δ2 agonist deltorphin II. Dexamethasone potentiated the antinociception induced by the k agonist, U50,488. 3 In experiments performed in an in vitro model of cerebral excitability in the rat hippocampal slice, dexamethasone strongly prevented both the increase of the duration of the field potential recorded in CA1, and the appearance and number of additional population spikes induced by μ receptor agonists. 4 In both models pretreatment with cycloheximide, a protein synthesis inhibitor, prevented the antagonism by dexamethasone of responses to the μ opioid agonists. 5 Our data indicate that in the rodent brain there is an important functional interaction between the corticosteroid and the opioid systems at least at the μ receptor level, while δ and k receptors are modulated in different ways.

Some Endorphin Derivatives and Hydrocortisone Prevent EEG Limbic Seizures Induced by Corticotropin-Releasing Factor in Rabbits

Summary: Corticotropin‐releasing factor (CRF) injected into the cerebral ventricles of small mammals induces EEG limbic seizures, behavioral excitability, stereotyped behavior, and tardive enhancement of hippocampal theta voltage and frequency. Because we addressed this phenomenon when we explained the pathogenesis of infantile spasms in children, we wished to study the interference exerted by some ‐β‐endorphin fragments on EEG epileptiform and behavioral symptoms induced by CRF in the rabbit. Animals were implanted intracerebroventricularly (i.c.v.) with semichronic cortical and hippocampal electrodes, together with a cannula into the left lateral ventricle. When some γ‐endorphin derivatives (DT‐γE, DEγE) were injected intravenously (i.v.) for 4 days (or hydrocortisone once), they prevented the EEG ictal seizures induced in the hippocampus of rabbits by CRF injected i.c.v. Hydrocortisone and DEγE also prevented the appearance of scattered spiking and partially prevented tardive enhancement of theta voltage in the hippocampal EEG. Finally, DEγE also prevented stereotyped behavior and excitability induced by CRF. These results confirm the regulatory role exerted by CRF in limbic structure excitability and suggest that the above peptides may be involved in a regulatory feedback mechanism of CRF metabolism or activity. The possibility that these peptides may also have interesting antiepileptogenic properties should be considered.

Effects of endorphin derivatives on the EEG alterations induced by corticotropin releasing factor in the rabbit hippocampus

Corticotropin releasing factor (CRF), injected into the cerebral ventricles (i.c.v.) of rabbits, induced EEG limbic seizures, behavioural excitability, stereotyped behaviour and the tardive enhancement of hippocampal theta voltage and frequency. The beta-endorphin cleavage derivatives des-tyr-gamma-endorphin (DT gamma E) and des-enkephalin-gamma-endorphin (DE gamma E), when injected i.v. for 4 days prevented the EEG ictal seizures induced by CRF in the hippocampus of rabbits and partly prevented the tardive enhancement of theta wave amplitude and frequency. These results suggest the possibility that these peptides may have antiepileptogenic properties.

Dexamethasone and Hormones Related to the Hypothalamic-Pituitary-Adrenal Axis Modulate Inherited Neocortical Spindling in DBA/2J Mice

The role of dexamethasone and hormones related to the hypothalamic-pituitary-adrenal (HPA) axis (corticotropin-releasing factor, adrenocorticotropic hormone, corticosterone) in the control of the spike-and-wave spindling episodes (S&W) which can be spontaneously recorded in the electrocorticogram (ECoG) of DBA/2J mice was investigated. Both dexamethasone and hormones related to the HPA axis consistently reduced the S&W in DBA/2J mice. Cycloheximide (a protein synthesis inhibitor) pretreatment significantly delayed the reducing effect of dexamethasone on the S&W in mice. After a transitory decrease, the glucocorticoid receptor antagonist RU-38486 induced a dramatic increase in the rate of the S&W episodes. In addition, mice treated with RU-38486 for 4 days showed a significant increase in the S&W 24 h after the 4th treatment. Our results indicate that dexamethasone as well as hormones related to the HPA axis are able to modulate the S&W in DBA/2J mice, suggesting that this effect may be bound to corticosteroid activity. The time lag (30-60 min) which is necessary for revealing the reducing influence of dexamethasone on the S&W in mice and the influence exerted by cycloheximide on dexamethasone activity support the hypothesis that the effect induced by dexamethasone may be at least in part dependent on genomic mechanisms.

Dexamethasone modifies the behavioral effects induced by clonidine in mice

The present study examines the influence of dexamethasone on behavioral effects induced by clonidine in mice. 2. The behavior elements considered were locomoter activity, rota rod, catalepsy and stereotyped behavior (rearing, grooming, social response test, crossing, smelling, washing face, scratching and bar holding). 3. Clonidine (0.1-0.5-1.0 mg/kg, IP) induced a significant reduction of all behavioral elements studied when compared to the saline treated group: the behavioral reduction was significant 10 min after administration and lasted for the entire recording period (120 min). 4. Dexamethasone (0.1-0.5-1.0 mg/kg, IP) per se did not induce significant changes in the behavior elements recorded. 5. Dexamethasone (0.1-0.5 mg/kg, IP) dod not affect behavioral effects induced by the 3 doses of clonidine, whereas the high dose (1 mg/kg) of the steroid significantly reduced its behavioral inhibition. 6. The results of the present study suggest that dexamethasone induces significant effects on clonidine-induced behavioral effects and that this may be related to an interference with the monoaminergic system.

Des-tyrosine-γ-endorphin effects on morphine analgesia in mice

Abstract 1. 1. The effects that were induced by a β-lipotropin fragment des-tyrosine-γ-endorphin (DTγE) devoid of opiate activity that was administered intraperitoneally or intracerebroventricularly to mice under morphine analgesia were investigated. The interaction of this peptide with the analgesic effects of morphine was examined using the hot plate and the tail flick test. 2. 2. Intraperitoneal acute treatment with DTγE did not change the analgesic effects of morphine. 3. 3. Intraperitoneal semi-chronic treatment performed for 4 days with DTγE enhanced morphine analgesic effects. 4. 4. The intracerebroventricular acute treatment with DTγE reduced morphine analgesia in a dose-dependent way. 5. 5. These results indicate that DTγE, although devoid of opioid activity per se , may interact with the opioid system, probably through an indirect mechanism.

Actinomycin D blocks the reducing effect of dexamethasone on amphetamine and cocaine hypermotility in mice.

1. The present study examined a time-course effect of dexamethasone (DEX) on amphetamine and cocaine-induced hypermotility in mice and the influence of actinomycin D (dactinomycin), a protein synthesis inhibitor, on DEX effects. 2. Amphetamine (5 mg/kg IP) and cocaine (10 mg/kg IP) increased markedly the locomotor activity of mice, whereas DEX alone (0.1-1.0-10 mg/kg IP) did not modify the activity of control mice. 3. DEX pretreatment 0, 15, 30, 60 and 120 min before amphetamine or cocaine strongly decreased both amphetamine and cocaine effects, but no dose-related effect was observed. 4. The time-course study performed with DEX revealed differences in its reducing effect on cocaine and amphetamine hypermotility when the groups of animals treated with the steroid immediately before the cocaine (or amphetamine) injection were compared to those treated with the steroid later (15, 30, 60 and 120 min). 5. Furthermore, actinomycin D was able to block the reducing effect of DEX on both amphetamine and cocaine hypermotility. 6. Therefore, considering that the administration time of the steroid seems to be an important factor for reducing both cocaine and amphetamine hypermotility, and actinomycin D was able to block the reducing effect of the steroid, our study suggests that DEX exerts its reducing effect through a genomic activation.

3-(3-hydroxyphenyl)-N-(1-propyl)piperidine elicits convulsant effects in mice

1. The behaviour and EEG effects of the dopamine and sigma (sigma) ligands (+) 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) were studied in mice. 2. (+) 3-PPP dose-dependently (60-100 mg/kg i.p.) produced behavioural and electrical tonic-clonic seizures. 3. The incidence of the tonic seizures elicited by 100 mg/kg of the drug was significantly (P < 0.05) prevented by spiperone (0.5 mg/kg i.p.) and haloperidol (0.5 mg/kg i.p.). 4. The results show an influence on the behavioural and electrical threshold of convulsions by (+) 3-PPP depending on a prevalent interference on dopamine receptors.

Time-related antiepileptic effects of the synthetic glucorticoid dexamethasone in rat hippocampal slices

The in vitro antiepileptic activity of the synthetic glucocorticoid dexamethasone (DEX) was tested in rat hippocampal slices on the CA1 epileptiform activity induced by sodium penicillin (PEN). Slice perfusion with 1 mM PEN produced within 60 min the development of a CA1 epileptiform bursting made up of an increase of the primary CA1 population spike followed by the appearance of secondary epileptiform population spikes. Slice perfusion with 100 microM DEX together with PEN (1 mM) partially prevented but did not block the expression of the CA1 epileptiform bursting as evidenced by a significant (P < 0.05) reduction of the duration of the bursting due to the epileptogenic agent. Slice perfusion with 50 microM DEX together with PEN (1 mM) failed to prevent or block the expression of the CA1 penicillin-induced epileptiform bursting. A 60 min slice pretreatment with 50-100 microM DEX followed by a slice perfusion with 50-100 microM DEX together with PEN (1 mM) prevented the expression of the CA1 epileptiform bursting. Cycloheximide (1 microM), a protein synthesis inhibitor, perfused together with DEX reverted the inhibitory effects of dexamethasone on the expression of the penicillin-induced CA1 epileptiform bursting. The results indicate that the synthetic glucocorticoid DEX presents concentration- and time-related in vitro antiepileptic effects. In addition, the data suggest that this inhibitory effect occurs via a protein synthesis-dependent mechanism.